Processes for preparing 6-hydroxy-3,4-dihydroquinolinone, cilostazol and N-(4-methoxyphenyl)-3-chloropropionamide

ABSTRACT

A process for preparing 6-hydroxy-3,4-dihydroquinolinone by intramolecular Friedel-Crafts alkylation of N-(4-methoxyphenyl)-3-chloropropionamide in which an equivalent of N-(4-methoxyphenyl)-3-chloropropionamide is contacted with a Lewis acid in DMSO or a high boiling amide or amine at an elevated temperature of from about 150° C. to about 220° C. is provided. The process produces 6-HQ in high yield and a high state of purity such that it may be used in subsequent reactions toward the preparation of cilostazol without intermediate purification. A process for preparing cilostazol from 6-hydroxy-3,4-dihydroquinolinone prepared by the process and improved processes for preparing N-(4-methoxyphenyl)-3-chloropropionamide are also provided.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This invention claims the benefit under 35 U.S.C. 1.119(e) ofprovisional application Serial No.60/190,588, filed Mar. 20, 2000.

FIELD OF THE INVENTION

[0002] The invention relates to therapeutic quinolinone derivatives suchas cilostazol and chemical intermediates useful for their preparation.The present invention also relates to 6-hydroxy-3,4-dihydroquinolinone,which is one such intermediate.

BACKGROUND OF THE INVENTION

[0003] The present invention pertains to6-hydroxy-3,4-dihydroquinolinone (“6-HQ”) of formula (I)

[0004] a known compound that is difficult to prepare on a large scalebecause of the sluggishness of the reaction by which it is preparedusing conveniently accessible starting materials and because of the needto maintain a high reaction temperature throughout the reactor. 6-HQ hascommercial importance as a key intermediate in the preparation ofcilostazol.

[0005] Cilostazol (6-[4-(1 -cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2( 1H)-quinolinone) is used totreat symptoms of intermittent claudication in patients suffering fromsymptoms of the disease, which include pain and cramping while walkingdue to reduced blood flow to the legs. Cilostazol has the chemicalstructure of formula (II).

[0006] Cilostazol is described in U.S. Pat. No. 4,277,479, which teachesthat it can be prepared by alkylating the phenol group of 6-HQ with a1-cyclohexyl-5-(4-halobutyl)-tetrazole of formula (III).

[0007] The first preparation of 6-HQ to appear in the U.S. patentliterature is Example 11D of U.S. Pat. No. 3,819,637 (the '637 patent).In Example 11D, 6-HQ is prepared by cyclization of(p-methoxyphenyl)-3-chloropropionamide (“MCPA”). A blend of MCPA andAlCl₃ was heated with rapid stirring to produce a melt and then furtherheated to 150° C. and held at that temperature for half an hour. Themelt was then poured into a slurry of cracked ice and hydrochloric acidto decompose the aluminum salts. 6-HQ was collected by filtration,washed with water and recrystallized from methanol. When these reactionconditions are scaled up, the high viscosity of the reaction mediumcauses temperature control problems. Cool regions form within thereactor and the 6-HQ and MCPA in those regions solidifies.Solidification hinders effective mixing of the reagents. Areas wherehigh concentrations of AlCl₃ are caused by inadequate mixing can become“hot spots” where thermal decomposition of the reactant and productoccur.

[0008] When we repeated the '637 process using 3 equivalents of AlCl₃,the reaction did not go to completion and we obtained the intermediateproduct N-(4-hydroxyphenyl)-3-chloropropionamide (“HPCA”) in 28% yield.Though most of the HPCA could be removed by recrystallization frommethanol as described in the '637 patent, 6-HQ could not be obtainedsubstantially free of contamination with HPCA. Reducing the amount ofAlCl₃ used in the reaction reduced the amount of HPCA but also reducedthe overall yield of 6-HQ. The reaction time also increased;nevertheless, the rapidity of the melt process with either 2 or 3equivalents of the catalyst is one of this method's merits.

[0009] The '637 process is a Friedel-Crafts alkylation. In contrast toFriedel-Crafts acylations, which have widespread utility, the usefulnessof Friedel-Crafts alkylations is limited by a tendancy towardover-alkylation of the aromatic participant, low aromaticregioselectivity and the tendency of carbocation intermediates torearrange. One of the most important uses of Friedel-Crafts alkylationis ring closure, which is less affected by these limitations thanintermolecular reactions are. There is an “intramolecular advantage”associated with generating the carbocation on the same molecule as thearomatic ring. The half-life of the carbocation is decreased by the highlocal concentration of the reacting partner, which minimizesrearrangement to a more stable secondary carbocation.

[0010] Despite the intramolecular advantage, cyclization of MCPA issluggish because the substitution must occur at a position on thearomatic ring ortho to an electron withdrawing group. An amido groupbonded to an aromatic ring through its nitrogen atom, like the amidegroup in MCPA, is ordinarily a weak activator of the ring towardelectrophilic aromatic substitution. However, in the cyclization ofMCPA, the amide carbonyl coordinates with AlCl₃. Coordination with AlCl₃converts the amide group into an electron withdrawing substituent anddeactivates the aromatic ring toward electrophilic substitution. Thedeactivating effect of a Lewis acid on aromatic ketones has beendescribed in Bull. Soc. Chim. Fr. 1984, 11, 285. In the '637 patent,high temperatures and the highest concentration attainable, i.e. a melt,were used to drive the cyclization onto the deactivated ring of MCPA.

[0011] The '637 patent also discloses in Example 11E a process forpreparing the Friedel-Crafts starting material MCPA by adding3-chloropropionyl chloride dropwise to a solution of p-anisidine in dryacetone.

[0012] Several investigators working in Japan have describedmodifications to the Friedel-Crafts reaction conditions of the '637patent.

[0013] According to Chemical Abstracts Doc. No. 127:34142, JapanesePatent No. 9-124605 describes an improved process in which the MCPA andAlCl₃ are diluted with a liquid paraffin in mixture with either DMSO oran amide. Suitable amides in the JP '605 process includeN,N-dimethylformamide (“DMF”) and N,N-dimethylacetamide (“DMA”). A 76.9%yield of 6-HQ is reported after 20 h at 105° C. in a mixture of paraffinand DMA. Suitable paraffins are C₇-C₁₄ hydocarbons. For a large scaleprocess, the lower molecular weight hydrocarbons are preferable foreconomic reasons. As an example, one liter of the C₇ hydrocarbonn-heptane costs less than a tenth as much of the C₁₂ hydrocarbondodecane.

[0014] In our hands and conducting the reaction in n-heptane and DMF at100° C., the yield was lower than claimed in the JP '605 patent. Thereaction also took longer but the purity of the product obtained afterrecrystallization from methanol and toluene was indeed improved over the'637 process. As is apparent from the Chemical Abstract, this processsuffers from a slow reaction rate.

[0015] According to Chemical Abstracts Doc. No. 133:585428, JapanesePatent No. 2000-229944, describes the AlCl₃ catalyzed cyclization ofMCPA in high boiling hydrocarbons like decahydronaphthalene andtetralin, and high boiling ethers like benzyl ethyl ether, isoamylether, diphenyl ether, diglyme and triglyme. Reaction of MCPA and AlCl₃for 8 h in decahydronaphthalene at 150° C. gave 6-HQ in 90% yield. TheJP '944 patent also discloses a preparation of MCPA from p-anisidine and3-chloropropionyl chloride in DMF, DMA, DMSO and diphenyl.

[0016] According to Chemical Abstracts Doc. No. 131:257448, JapanesePatent No. 11-269148 describes the Friedel-Crafts intramolecularalkylation of MCPA in a mixture of a halobenzene and an amide or amine.The reaction may be performed at between 110° C. and 200° C. with 0.1 to10 equivalents of amine. It is reported that 6-HQ was obtained in 78%yield after fifteen hours at 130° C. in a mixture o-dichlorobenzene andtrioctylamine.

[0017] Aromatic solvents like benzene and tetralin are usually a poorsolvent choice for conducting Friedel-Crafts alkylation reactionsbecause the solvent, which is usually present in large excess, issusceptible to electrophilic attack. Halobenzenes like o-dichlorobenzeneare somewhat deactivated towards electrophilic attack and, as mentioned,there is an intramolecular advantage favoring the Friedel-Craftsalkylation of MCPA. However, since the aromatic ring of MCPA is alsodeactivated, it was found that reaction with solvent was competitivewith cyclization. The side products of reactions with solvent weredetected as a complex pattern of peaks in the HPLC chromatogram of theproduct mixture that was absent from the chromatograms of the productmixtures from the melt and paraffin processes.

[0018] It would be desirable to have a process for making 6-HQ in a highlevel of purity, by a reaction that proceeds at a fast rate and with animprovement in the yield.

SUMMARY OF THE INVENTION

[0019] The present invention provides a process for preparing6-hydroxy-3,4-dihydroquinolinone by intramolecular Friedel-Craftsalkylation of N-(4-methoxyphenyl)-3-chloropropionamide in which anequivalent of N-(4-methoxyphenyl)-3-chloropropionamide is contacted withabout 3 to about 5 equivalents of a Lewis acid in DMSO or a high boilingamide or amine at an elevated temperature of from about 150° C. to about220° C. A highly concentrated reaction mixture causes a fast reactionrate yet remains fluid throughout the reaction. The process produces6-HQ in high yield and a high state of purity such that it may be usedin subsequent reactions toward the preparation of cilostazol withoutintermediate purification. The present invention further provides aprocess for preparing cilostazol from 6-HQ prepared by the process.Improved processes for preparingN-(4-methoxyphenyl)-3-chloropropionamide are also provided.

DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention provides an improved process for preparing6-hydroxy-3,4-dihydroquinolinone (I) fromN-(4-methoxyphenyl)-3-chloropropionamide (IV). The transformation fromstarting material to product involves a ring closure and a demethylationof the phenol group as depicted in Scheme 1.

[0021] addition of a paraffin, halogenated aromatic or high boilingether, and thus neither these substances nor any others are added to thereaction in amounts that would increase the reaction time beyond about 3hours. Another important aspect of the invention is that despite thehigh concentration, it is less prone to solidification due to variationsin temperature at different locations within the reactor than a melt is.The diluents of this invention maintain the fluidity of the reactionmixture even at high concentration. As discussed below, a reactionmixture in DMA slurries as the reaction nears completion, but the slurryis easily stirred and does not cause hot spots.

[0022] The process is further illustrated with an illustrative step-wisedescription of the process in which the catalyst is AlCl₃ and thesolvent is DMA. The process may be performed in a reactor equipped witha heater, paddle stirrer, powder funnel, thermometer and vaporcondensor. The reactor is charged with MCPA and 1.3 equivalents of DMA.The powder funnel is charged with 4 equivalents of AlCl₃. AlCl₃ is addedslowly while stirring the cloudy mixture and monitoring the thermometeror reflux rate for excessive exotherm. Preferably, the temperatureshould not be allowed to exceed about 160° C. during the addition. If arapid exotherm occurs, control of the temperature may be regained byshutting off the flow of AlCl₃ and allowing reflux to cool the reactoror by cooling the reactor externally. After completing the addition,progress of the reaction may be monitored by TLC (eluent: (12:8:2:2)MEK:CHCl₃:CH₂Cl₂:IPA; R_(f)(6-HQ)=0.5). One indication that the reactionis nearing completion is that the mixture which originally was aslightly cloudy solution becomes a slurry. The slurry is easily stirredand does not contribute to hot spot formation in the reactor. Thereaction typically takes another 30 minutes to 2 hours to go tocompletion after the addition of AlCl₃ is complete.

[0023] The reaction may be quenched by slowly pouring the reactionmixture into aqueous or alcohol solution in a well ventilated area andthen decomposing the aluminum salts with sodium borohydride andrecovering 6-HQ by filtration. The aluminum salts also can be decomposedwith hydrochloric acid.

[0024] The 6-HQ obtained by practicing the foregoing process may be usedto prepare cilostazol by the novel method disclosed in U.S. patentapplication Ser. No. [attorney docket No. 1662/52104], which is herebyincorporated by reference in its entirety. The 6-HQ obtained bypracticing the foregoing process also may be used to prepare cilostazolby other methods, such as the method described in U.S. Pat. No.4,277,479, which is herein incorporated by reference for its teaching ofthe preparation of 3,4-dihydroquinolinone derivatives from 6-HQ.According to the '479 patent's method, 6-HQ is dissolved in ethanolcontaining DBU. 1-Cyclohexyl-5-(4-iodobutyl)-tetrazole is added dropwiseto the refluxing solution over ninety minutes and the reaction mixtureis refluxed for another 5 hours. The mixture is then concentrated andtaken up in chloroform which is washed with dilute NaOH, dilute HCl andwater. The organic phase is then dried over sodium sulfate andevaporated. The residue is recrystallized from an ethanol and watermixture to give cilostazol having a melting point of 148-150.5° C.

[0025] The MCPA (IV) starting material for preparing 6-HQ may beprepared by improved acylation processes which produce MCPA in highyield and high purity which is suitable for use to prepare 6-HQ withoutchromatographic purification. Comparision of the results in Table 2 ofthe Examples shows that the following processes produce MCPA with puritycomparable to the product obtained from the process of the '637 patentbut in a higher yield. The transformation from starting materials toproduct involves an acylation of p-anisidine with 3-chloropropionylchloride as depicted in Scheme 2.

[0026] The improvement over known processes for acylating p-anisidinewith 3-chloropropionyl chloride resides in the base/solvent combinationsused in the processes and the reaction conditions, particularlytemperature, which provide the optimum yields and purity with theparticular solvent/base combination.

[0027] In the most preferred of these processes, p-anisidine isdissolved in a sufficient amount of toluene to produce an approximately3 to 5 M solution, more preferably about 4 M solution. Between 1 and 2equivalents, more preferably about 1.5 equivalents, of sodiumbicarbonate (“NaHCO₃”) are suspended in the p-anisidine solution and theresulting suspension is stirred while an approximately equivalent amount3-chloropropionyl chloride (i.e. 1-1.2 eq.) is added dropwise to thestirred suspension. The addition may be conducted at reduced or ambienttemperature and the temperature may be allowed to rise, but should notbe allowed to exceed 70° C. After completing the addition, thetemperature of the reaction is maintained at between room temperatureand the reflux temperature of toluene (111° C.), most preferrably about60° C., for a time sufficient for the reaction to be complete. Progressof the reaction may be monitored by TLC using the method described inExample 2a. After the reaction is complete, the reaction mixture isquenched with water or aqueous mineral acid and MCPA is isolated fromthe resulting suspension by filtration, decantation and the like,preferably filtration. The MCPA is then washed with water, toluene, orother nonviscous liquid in which the MCPA is not substantially soluble.The washed solid is then dried.

[0028] In another acylation process, N,N-dimethylformamide (“DMF”)fulfills the function of solvent and acid scavenger. p-Anisidine isdissolved in an amount of DMF to produce an approximately 2 to 3 Msolution, more preferably about 2.7 M solution of p-anisidine in DMF.The from 1 to 1.2 equivalents of 3-chloropropionyl chloride are added tothe solution. The reaction proceeds smoothly to completion in about 4hours without external heating. MCPA may then be isolated from thereaction mixture by the method described with reference to thetoluene/NaHCO₃ process.

[0029] In an alternative acylation process which gives MCPA in highpurity, albeit in lower yield than the toluene/NaHCO₃ process,p-anisidine is dissolved in sufficient methyl ethyl ketone (“MEK”) togive an approximately 3 to 5 M solution, preferably about 4 M. Between0.9 and 1.2 equivalents of triethyl amine (“Et₃N”) is added to thesolution as acid scavenger followed by slow addition of between 0.9 and1.2 equivalents of 3-chloropropionyl chloride. As previously describedwith reference to the toluene/NaHCO₃ process, the addition may beconducted at reduced or ambient temperature and the temperature may beallowed to rise, but should not be allowed to exceed 70° C. Aftercompleting the addition, the solution is refluxed (80° C.) for a timesufficient to complete the reaction which may be determined by TLC usingthe method described in Example 2a. MCPA is then isolated from thereaction mixture as described with reference to the toluene/NaHCO₃process.

[0030] In yet another acylation process, p-anisidine is dissolved insufficient dichloromethane to produce an approximately 2 to 4 Msolution, more preferably about 3 M solution of p-anisidine.Approximately one equivalent of aqueous sodium hydroxide andapproximately one equivalent of 3-chloropropionyl chloride are thenadded slowly and simultaneously to the solution so as to maintain anapproximately neutral pH in the organic phase. The addition ispreferrably performed at controlled low temperature of 0° C. or less.The reaction may be quenched and the MCPA product may be isolated by themethods described with reference to the toluene/NaCO₃ process.

[0031] The following specific examples are provided to furtherillustrate the practice of the present invention. It is not intendedthat the invention be limited in any way by these examples which areprovided for the purpose of illustration only.

EXAMPLES General

[0032] p-Anisidine of 99% purity and 3-chloropropionyl chloride of 98%purity were used as received from Acros Organics. Other reagents andsolvents were also used as received.

[0033] High performance liquid chromatography (“HPLC”) was performedusing the following conditions: column and packing Zorbax® RX-C₈ 250×4.6mm, 5 μm; UV detection: λ=254 nm; flow rate: 1 ml/min linear gradient;gradient elution: solvent A=0.02 M trisodium citrate dihydrate in wateradjusted to pH 5.3 with 0.07 M citric acid (˜100 ml), solventB=acetonitrile. The gradient program is shown below. Time (min) Eluent A(%) Eluent B (%)  0 85 15 40 50 50

Example 1 Preparation of 6-hydroxy-3,4-dihydroquinolinone

[0034] N-(4-methoxyphenyl)-3-chloropropionamide (300 g, 1.4 mol.) andN,N-dimethylacetamide (165 ml, d=0.937, 1.3 eq.) were added to athree-necked, three-liter flask. Trichloroaluminum (760 g, 4 eq.) wasslowly added over two hours. An exotherm raised the temperature of themixture from about 25 ° C. to 140° C. over the course of the addition.The reaction mixture was a slightly cloudy colorless solution. Thesolution was stirred and held at 150-160° C. for two hours. At the endof the two hours the reaction mixture had become a stirrable slurry. Themixture was then cooled to ambient temperature and quenched by pouringinto water (5.5 L) in a fume hood with good circulation and a trapbetween the inlet and the exhaust to capture evolved HCl gas. Next,sodium borohydride (30 g) was added, which caused the mixture color toturn from gray to white. The mixture was then cooled to ambienttemperature and filtered. The collected solids were washed with water (2L) and dried overnight in a vacuum-oven at 60° C. to give6-hydroxy-3,4-dihydroquinolinone (212.8 g, 92.9%) in 99.2% purity basedon HPLC analysis.

[0035] As shown in Table 1, entries 2-4, when 1.3 equivalents of DMA wasused, the reaction was reproducible, giving 6-HQ in an average yield of91.6% and an average purity of 98.9%. As also shown in Table 1, entry 1,reduction of the DMA content to 1 equivalent caused a reduction in yieldand increase in HCPA content of the product but nevertheless produced asuperior product compared to the methods known to the art. Cyclizationof MCPA in the highly concentrated solutions according to the presentinvention produces 6-HQ in improved yield and higher purity than doescyclization in a melt (compare Table 1 entries 1-4 with entries 5 and6). These improvements are achieved without the significant increase inreaction time observed when the reaction is conducted in paraffin or ahalobenzene (compare Table 1, entries 1-4 with entries 7 and 8). TABLE 1Purity Analysis Reaction Medium 6-HQ Compound (% area) Entry AlCl₃ (eq.)1st Diluent (eq.) 2nd Diluent Temp. (° C.) Time (h) % Yield 6-HQ HCPAN—CH₃-6-HQ^(a) MCPA 6-MQ^(b) 1 4 DMA(1) — 150 2.5 83.6 97.9 0.07 2 4DMA(1.3) — 150-160 2 94.4 98.8 0 0.2 0.12 0.11 3 4 DMA(1.3) — 150-160 292.9 99.2 0.06 0.06 0.23 4 4 DMA(1.3) — 150-160 2 87.5 98.7 0.05 0.150.42 5 3 — — 160 0.5 88.8 70.6 28.3 (compara- (60)^(d) (94.9)^(d)(4.25)^(d) (0.14)^(d) tive^(c)) 6 2 — — 150 2 80.8 98.7 0.09 (compara-tive^(c)) 7 2 DMF(1) o-dichloro- 130 6 79.2 73.7^(f) 0.03 (compara-benzene tive^(e)) 8 3.5 DMF(1.1) n-heptane 100 26 60 96.4 0.12 (compara-(96.4)^(h) (1.7)^(h) (0.12)^(h) (0.12)^(h) tive^(g))

Example 2a Preparation of N-(4-methoxyphenyl)-3-chloropropionamide inToluene/NaHCO₃

[0036] p-Anisidine (200 g) and NaHCO₃ (205 g) were added to toluene (400ml) in a three-liter, three-necked flask. A solution of3-chloropropionyl chloride (207.5 g) in toluene (400 ml) was addeddrop-wise over an hour and a half to the mixture and the temperature ofthe reaction mixture was allowed to rise to 50° C. After completing theaddition, the reaction mixture was heated to 60° C. for about one hour.The reaction was monitored by TLC (eluent: (12:8:2:2)MEK:CHCl₃:CH₂Cl₂:IPA). The mixture was cooled to ambient temperature.Concentrated hydrochloric acid (100 ml) was diluted 10 to 1 with waterand added to the mixture over thirty minutes at ambient temperature. Themixture was filtered and the collected salts were washed with water (500ml), and then toluene (250 ml). The resulting product was driedovernight at 60° C. The dried product wasN-(4-methoxyphenyl)-3-chloropropionamide (334 g, 96.2%) in 99.65% purityby HPLC analysis.

Example 2b Preparation of N-(4-methoxyphenyl)-3-chloropropionamide inMEK/Et₃N

[0037] A three-necked flask was charged with p-Anisidine (50 g), Et₃N(40.43 g) and methyl ethyl ketone (100 ml). The resulting slurry wascooled to 10° C. and 3-chloropropionyl chloride (50.74 g) was slowlyadded. The temperature was allowed to rise to 60° C. during theaddition. The mixture was then refluxed for 1 hour and cooled to 50° C.The solids were collected by filtration, washed with water, and dried at50° C. to constant weight to giveN-(4-methoxyphenyl)-3-chloropropionamide (56.42 g, 86.8%).

Example 2c Preparation of N-(4-methoxyphenyl)-3-chloropropionamide inDMF

[0038] p-Anisidine (10 g) was dissolved in DMF (30 ml).3-Chloropropionyl chloride (10.12 g) was added at ambient temperatureand the solution was stirred for about four hours. The reaction mixturewas quenched with water. The solid product was isolated by filtrationand dried under vacuum at 60° C. to give MCPA (13.05 g, 76.7%) in 99.5%purity based upon HPLC analysis.

Example 2d Preparation of N-(4-methoxyphenyl)-3-chloropropionamide inCH₂Cl₂/NaOH

[0039] p-Anisidine (12.3 g) was dissolved in CH₂Cl₂ (30 ml) and thesolution was cooled to 5° C. Aqueous NaOH (6.6 g in 13 ml water) and3-chloro-propionyl-chloride (19.05 g) were simultaneous added to theabove solution over 40 minutes. The two phase mixture was stirred at 5°C. for another 30 min. Water (250 ml) and concentrated HCl (3 ml) werethen added. The product was isolated by filtration, washed with waterand dried to a constant weight to giveN-(4-methoxyphenyl)-3-chloropropionamide (29.7 g, 94.6%) in 99.3% purityby HPLC analysis. TABLE 2 Equivalents of ρ-Anisidine Solvent Base Temp.(° C.) % Yield % Purity (comparative^(a)) acetone — reflux 88 99.5 2 1MEK Et₃N reflux 86.8 n.d.^(b) 1.2 DMF — r.t. 76.7 99.5 1 CH₂Cl₂ NaOH −594.5 99.3 1 Toluene NaHCO₃ 60 94.2 99.5 1 Toluene NaHCO₃ 60 96.5 99.6 1Toluene NaHCO₃ 60 96.2 99.7

[0040] As can be seen from the results summarized in Table 2, acylationof p-anisidine with 3-chloropropionyl chloride in toluene with NaHCO₃ asacid scavenger consistently gave high yields and high purity of MCPAwithout chromatographic purification or recrystallization. Conduct ofthe reaction in MEK, DMF and CH₂Cl2 according to Examples 2b-d providesalternative processes for making MCPA with their own distinct advantagessuch as operating at reduced or ambient temperature.

[0041] Having thus described the present invention with reference tocertain preferred embodiments and illustrated it with examples, oneskilled in the art will recognize variations and substitutions in themethods as described and exemplified which do not depart from the spiritand scope of the invention as defined by the claims which follow.

We claim:
 1. A process for preparing 6-hydroxy-3,4-dihydroquinolinone bycyclization of N-(4-methoxyphenyl)-3-chloropropionamide comprising thesteps of: a) contacting an equivalent ofN-(4-methoxyphenyl)-3-chloropropionamide with about 3 to about 5equivalents of a Lewis acid catalyst in a diluent selected from thegroup consisting of dimethyl sulfoxide, N,N-disubstituted amides andamines having a boiling point of 150° C. or above, the diluent beingpresent in an amount of from about 1 to about 1.3 equivalents withrespect to the N-(4-methoxyphenyl)-3-chloropropionamide, at an elevatedtemperature of from about 150° C. to about 220° C. for a period of timesufficient to cause substantially all of theN-(4-methoxyphenyl)-3-chloropropionamide to cyclize and demethylateresulting in the formation of a Lewis acid salt of6-hydroxy-3,4-dihydroquinolinone, and thereafter, b) decomposing theLewis acid salt of 6-hydroxy-3,4-dihydroquinolinone, and c) isolating6-hydroxy-3,4-dihydroquinolinone.
 2. The process of claim 1 wherein theLewis acid is selected from the group consisting of AlCl₃, AlBr₃, FeCl₃,FeBr₃, SbF₅, TiCl₄, SnCl₄ and BF₃.
 3. The process of claim 2 wherein theLewis acid is AlCl₃.
 4. The process of claim 3 wherein theN-(4-methoxyphenyl)-3-chloropropionamide is contacted with about 4equivalents of AlCl₃.
 5. The process of claim 1 wherein the timesufficient to cause substantially all of theN-(4-methoxyphenyl)-3-chloropropionamide to cyclize is three hours orless.
 6. The process of claim 1 wherein theN-(4-methoxyphenyl)-3-chloropropionamide and Lewis acid are contacted atan elevated temperature of from about 150° C. to about 160° C.
 7. Theprocess of claim 1 and thereafter converting the6-hydroxy-3,4-dihydroquinolinone to6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinoneor a pharmaceutically acceptable salt thereof.
 8. The process of claim 7wherein the conversion of 6-hydroxy-3,4-dihydroquinolinone to6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinoneor a pharmaceutically acceptable salt thereof is by reaction of6-hydroxy-3,4-dihydroquinolinone with a1-cyclohexyl-5-(4-halobutyl)-tetrazole in the presence of an organic orinorganic base.
 9. 6-Hydroxy-3,4-dihydroquinolinone prepared by theprocess of claim
 1. 10. A process for preparing6-hydroxy-3,4-dihydroquinolinone by cyclization ofN-(4-methoxyphenyl)-3-chloropropionamide comprising the steps of: a)contacting an equivalent of N-(4-methoxyphenyl)-3-chloropropionamidewith about 3 to about 5 equivalents of a Lewis acid catalyst in areaction medium consisting essentially of a diluent selected from thegroup consisting of dimethyl sulfoxide, N,N-disubstituted amides andamines having a boiling point of 150° C. or above, the diluent beingpresent in an amount of from about 1 to about 1.3 equivalents withrespect to the N-(4-methoxyphenyl)-3-chloropropionamide, at an elevatedtemperature of from about 150° C. to about 220° C. for a period of timesufficient to cause substantially all of theN-(4-methoxyphenyl)-3-chloropropionamide to cyclize and demethylateresulting in the formation of a Lewis acid salt of6-hydroxy-3,4-dihydroquinolinone, and thereafter, b) decomposing theLewis acid salt of 6-hydroxy-3,4-dihydroquinolinone, and c) isolating6-hydroxy-3,4-dihydroquinolinone.
 11. 6-Hydroxy-3,4-dihydroquinolinoneprepared by the process of claim
 10. 12. A process for preparingN-(4-methoxyphenyl)-3-chloropropionamide comprising the steps of addingp-anisidine and from about 1 to 1.2 equivalents of sodium bicarbonatewith respect to the p-anisidine to toluene to form a suspension ofsodium bicarbonate in a p-anisidine solution, slowly adding from about0.9 to about 1.1 equivalents of 3-chloropropionyl chloride to thesuspension, maintaining the temperature of the suspension at from about25° C. to about 111° C. for a period of time sufficient to causesubstantially all of the p-anisidine to be converted toN-(4-methoxyphenyl)-3-chloropropionamide, quenching the mixture withaqueous mineral acid, wherein quenching causes precipitation of solid,and isolating the solid from the quenched mixture, further wherein afterwashing with water and toluene, followed by drying to a constant weight,the solid that is obtained is N-(4-methoxyphenyl)-3-chloropropionamidein greater than 98% purity.
 13. N-(4-methoxyphenyl)-3-chloropropionamidemade by the process of claim
 12. 14. A process for preparingN-(4-methoxyphenyl)-3-chloropropionamide comprising the steps of addingp-anisidine and from about 1 to 1.2 equivalents of triethylamine withrespect to the p-anisidine to methyl ethyl ketone, slowly adding fromabout 0.9 to about 1.1 equivalents of 3-chloropropionyl chloride,heating the resulting mixture to reflux temperature, precipitating asolid from the reaction mixture by cooling, and isolating the solid fromthe mixture, wherein after washing with water and drying to constantweight the solid that is obtained isN-(4-methoxyphenyl)-3-chloropropionamide in greater than 98% purity. 15.N-(4-methoxyphenyl)-3-chloropropionamide made by the process of claim14.
 16. A process for preparing N-(4-methoxyphenyl)-3-chloropropionamidecomprising the steps of dissolving p-anisidine in dichloromethane toform a N-(4-methoxyphenyl)-3-chloropropionamide solution and adding fromabout 0.9 to about 1.1 equivalents of 3-chloropropionyl chloride andfrom about 0.9 to about 1.1 equivalents sodium hydroxide at atemperature of 0° C. or less and in a concerted manner that maintainsapproximately neutral pH in the (4-methoxyphenyl)-3-chloropropionamidesolution, precipitating a solid from the dichlormethane phase of theresulting two phase mixture and separating the solid from thedichloromethane, wherein after washing with water and drying to constantweight the solid that is obtained isN-(4-methoxyphenyl)-3-chloropropionamide in greater than 98% purity. 17.N-(4-methoxyphenyl)-3-chloropropionamide made by the process of claim16.
 18. A process for preparing N-(4-methoxyphenyl)-3-chloropropionamidecomprising the steps of dissolving p-anisidine in N,N-dimethylformamideand adding from about 0.9 to about 1.1 equivalents 3-chloropropionylchloride with respect to the p-anisidine to the solution for a timesufficient to form N-(4-methoxyphenyl)-3-chloropropionamide, addingwater to the mixture, whereupon addition of the water causes a solid toprecipitate from the mixture, isolating the solid from the mixture,wherein after washing with water and drying to a constant weight thesolid is N-(4-methoxyphenyl)-3-chloropropionamide in greater than 98%purity.
 19. N-(4-methoxyphenyl)-3-chloropropionamide made by the processof claim 18.